Gene hunting in autism spectrum disorder: on the path to precision medicine

Abstract

Autism spectrum disorder is typical of the majority of neuropsychiatric syndromes in that it is defined by signs and symptoms, rather than by aetiology. Not surprisingly, the causes of this complex human condition are manifold and include a substantial genetic component. Recent developments in gene-hunting technologies and methods, and the resulting plethora of genetic findings, promise to open new avenues to understanding of disease pathophysiology and to contribute to improved clinical management. Despite remarkable genetic heterogeneity, evidence is emerging for converging pathophysiology in autism spectrum disorder, but how this notion of convergent pathways will translate into therapeutics remains to be established. Leveraging genetic findings through advances in model systems and integrative genomic approaches could lead to the development of new classes of therapies and a personalised approach to treatment.

Figure 1. A model of the effects of gene sets implicated in autism spectrum disorder

(A) Autism spectrum disorder (ASD) risk genes from several sources, including mutations identified by exome sequencing^,,, of candidate genes from the Simons Foundation Autism Research Initiative (SFARI) database and neuronal genes dysregulated in the post-mortem brains of people with ASD, were compiled as described in detail by Parikshak and colleagues. ASD risk genes were differentially enriched in five co-expression modules throughout development: M2, M3, M13, M16, and M17. (B) Early transcriptional regulators in M2/M3 are enriched for rare de novo variants (RDNVs), whereas the later-expressed synaptic genes in M13, M16, and M17 are associated with previously studied ASD candidate genes compiled in the SFARI database and dysregulated in the post-mortem brain tissue from patients diagnosed with an ASD. By contrast with ASD genes, more than 400 known mendelian intellectual disability (ID) risk genes compiled from multiple sources were not enriched for specific developmental trajectories. (C) By using publicly available gene expression data from specific cell types or cortical laminae, ASD risk genes were found to be more consistently associated with post-mitotic laminae during early fetal development (IZ, SP, CPo/CPi, and MZ) and upper cortical layers in adults (L2 or L3, and RDNV-associated genes in L4). Several gene co-expression modules that correspond to specific processes in brain development that are enriched for ASD genes are also strongly associated with markers of upper-layer glutamatergic neurons in adult cortex, which suggests that many ASD genes preferentially affect these cell types. Work from Willsey and colleagues identified a subset of genes enriched in lower-layer neurons, but overall supported enrichment in glutamatergic neurons. SNV=single-nucleotide variant. MZ=marginal zone. CPo=outer cortical plate. CPi=inner cortical plate. SP=subplate zone. IZ=intermediate zone. SZi=inner subventricular zone. VZ=ventricular zone. Adapted with permission from Parikshak and colleagues.

Figure 2. Developmental and regional expression patterns of newly identified recurrently mutated risk genes in autism spectrum disorder

Heat map depicting gene expression patterns in various brain regions throughout development for each of the recurrently mutated autism spectrum disorder (ASD) risk genes depicted in the table, using gene expression data adapted from Kang and colleagues. The colour code is scaled from red (high expression) to blue (low expression). Developmental stages range from post-conception week 4–8 (stage 1) and mid-gestation (stages 4–6), through birth to 6 months (stage 8), and into adulthood (stage 13 and beyond). Most genes have very circumscribed developmental gradients of expression, showing either high fetal expression (eg, chromatin and transcriptional regulatory genes) or a postnatal increase concomitant with neuronal maturation (eg, synaptic signalling genes). DFC=dorsolateral prefrontal cortex. M1C=primary motor (M1) cortex. IPC=inferior parietal cortex. ITC=inferior temporal cortex.